The role of estrogen in heart disease remains extremely controversial. Large randomized trials of hormone replacement therapy have failed to show a reduction in heart attacks or strokes with certain hormone replacement preparations, however it appears likely that the design of these trials was not suitable to answer critical questions. In contrast, data continues to accumulate which provides strong evidence that estrogen is a key mediator of important processes including repair of damaged heart and vascular tissues and of the protective effect that irrefutably exists during pre-menopausal life. Studies in both humans and animals have established that a family of proteins, known as the "Hedgehog" signaling pathway, regulates the growth and development of certain organs. Experiments performed in animals show that the Hedgehog pathway may be recapitulated in adult regenerating tissues. Very recently we have demonstrated that "Sonic" hedgehog is induced by estrogen and thereby exerts an indirect effect by inducing blood vessel formation in cardiac and other tissues that lack an adequate blood supply. This appears to be the result of the upregulation of multiple families of angiogenic growth factors. Accordingly, this proposal will further investigate the role of the Hedgehog pathway in mediating the effects of estrogen in repair and regeneration of ischemic and injured tissues in clinically relevant models. The ultimate goal of these studies is to identify future clinical strategies for tissue repair.